Sepsis is an endotoxin-mediated disorder and the most common cause of acute lung injury (ALI) (MacCallum and Evans, (2005) Current Opinion In Critical Care 11: 43-49), a syndrome with a high mortality rate (Rubenfeld et al., (2005) New England Journal Of Medicine 353: 1685-1693; Levy et al., (2005) Critical Care 9: R502-R507.2, 3). Sepsis is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea and organ dysfunction. Sepsis can result from septicemia (i.e., organisms, their metabolic end-products or toxins in the blood stream), including bacteremia (i.e., bacteria in the blood), as well as toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxin in the blood). The term “bacteremia” includes occult bacteremia observed in young febrile children with no apparent foci of infection. The term “sepsis” also encompasses fungemia (i.e., fungi in the blood), viremia (i.e., viruses or virus particles in the blood), and parasitemia (i.e., helminthic or protozoan parasites in the blood). Thus, septicemia and septic shock (acute circulatory failure resulting from septicemia often associated with multiple organ failure and a high mortality rate) may be caused by a number of organisms. The systemic invasion of microorganisms presents two distinct problems. First, the growth of the microorganisms can directly damage tissues, organs, and vascular function. Second, toxic components of the microorganisms can lead to rapid systemic inflammatory responses that can quickly damage vital organs and lead to circulatory collapse (i.e., septic shock) and oftentimes, death.
Cbl proteins have evolutionarily conserved roles in regulating protein tyrosine kinases (Thien and Langdon, (2001) Nature Reviews Molecular Cell Biology 2: 294-305), down-regulating activated receptor tyrosine kinases (Levkowitz et al., (1998) Genes & Development 12: 3663-3674; Yoon et al., (1995) Science 269: 1102-1105; Haglund and Dikic, (2005) EMBO Journal 24: 3353-3359; Haglund et al., (2003) Nature Cell Biology 5: 461-466), and removing activated antigen receptors from the cell surface (Naramura et al., (2002) Nature Immunology 3: 1192-1199). E3 ubiquitin-protein ligase Casitas B-lineage lymphoma proto-oncogene b (Cblb ), in particular, regulates adaptive immunity by setting activation thresholds of mature lymphocytes (Chiang, et al., (2000) Nature 403: 216-220; Bachmaier et al., (2000) Nature 403: 211-216; Krawczyk et al., (2000) Immunity 13: 463-473), and is necessary for the induction of T cell tolerance (Jeon et al., (2004) Immunity 21: 167-177). Toll-like receptors (TLRs) are pattern-recognition receptors that have evolved to protect their possessors from microbial infection (Janeway and Medzhitov, (2002) Annual Review Of Immunology 20: 197-216), and TLRs are important for the induction of adaptive immune responses (Takeda et al., (2003) Annual Review Of Immunology 21: 335-376). TLRs also mediate, however, the adverse effects of microbial infection. For example, endotoxins of gram-negative bacteria (lipopolysaccharide (LPS)) signaling through TLR4 cause inflammation resulting in ALI (Beutler and Poltorak, (2001) Critical Care Medicine 29: S2-S6). LPS is the major component of the outer membrane of gram-negative bacteria and is responsible for many of the pathophysiological effects observed during infections with gram-negative pathogens that may lead to septic shock and death (E. T. Rietschel et al., (1992) Scient. Amer. 267: 54; (1994) FASEB J. 8: 217). Enterobacterial LPS consists of three domains, i.e., lipid A, core region and O-specific chain, of which lipid A is structurally the most conserved among different pathogenic bacteria, and represents the toxic principle of LPS(C. A. H. Raetz, (1990) Ann. Rev. Biochem. 59: 129; E. T. Reitschel et al., (1991) Infect. Dis. Clin. North Am. 5: 753; C. Galanos et al., (1985) Eur. J. Biochem. 148: 1). As the toxic effects exerted by LPS are independent of the viability of bacteria and considering the increasing resistance of pathogenic bacteria to antibiotics, the search for alternative treatment strategies for an endotoxin-mediated disorder is of major importance.
Receptors of adaptive and innate immunity share signaling pathways and antigen receptors may have evolved from microbial pattern-recognition receptors (Litman et al., (1999) Annual Review Of Immunology 17: 109-147; Liew et al., (2005) Nature Reviews Immunology 5: 446-458). Cblb expression has also been shown to be up-regulated with monocyte differentiation of HL60 and U937 cell lines (Keane et al., (1995) Oncogene 10: 2367-2377), suggesting its potential importance in the innate immune response.
Thus there exists a need in the art for methods of treating or preventing an endotoxin-mediated disorder.